Design and synthesis of antiangiogenic/heparin-binding arginine dendrimer mimicking the surface of endostatin.

We designed and synthesized the antiangiogenic arginine-rich dendrimers, TX-1943 and TX-1944, which mimic the surface structure of endostatin. TX-1944 containing 16 arginine residues is more similar in surface structure to endostatin than TX-1943 with eight arginine residues, and has stronger in vivo antiangiogenic activity at 10 microg/CAM in the chicken embryo chorioallantoic membrane (CAM) assay. TX-1944 also has stronger activity to bind heparin and to inhibit the growth of rat lung endothelial (RLE) cells than TX-1943.

[1]  H. Nagasawa,et al.  New antimetastatic hypoxic cell radiosensitizers: design, synthesis, and biological activities of 2-nitroimidazole-acetamide, TX-1877, and its analogues. , 2001, Bioorganic & medicinal chemistry.

[2]  B. Döme,et al.  Effect of HGF-like basic hexapeptides on angiogenesis. , 2001, Microvascular research.

[3]  Lars Holmgren,et al.  Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma , 1994, Cell.

[4]  William A. Goddard,et al.  Starburst Dendrimers: Molecular‐Level Control of Size, Shape, Surface Chemistry, Topology, and Flexibility from Atoms to Macroscopic Matter , 1990 .

[5]  J. Folkman.  Angiogenesis in cancer, vascular, rheumatoid and other disease , 1995, Nature Medicine.

[6]  William Arbuthnot Sir Lane,et al.  Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth , 1997, Cell.

[7]  Jeffrey D. Esko,et al.  Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor , 1991, Cell.

[8]  J. Williamson,et al.  Angiogenesis: new targets for the development of anticancer chemotherapies. , 2000, Current pharmaceutical design.

[9]  H. Hori,et al.  Design, synthesis, and biological activity of anti-angiogenic hypoxic cell radiosensitizer haloacetylcarbamoyl-2-nitroimidazoles. , 1997, Bioorganic & medicinal chemistry.

[10]  Y. Gho,et al.  Arginine-rich Anti-vascular Endothelial Growth Factor Peptides Inhibit Tumor Growth and Metastasis by Blocking Angiogenesis* , 2000, The Journal of Biological Chemistry.

[11]  A. Harris,et al.  Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[12]  M. Klagsbrun.  Mediators of angiogenesis: the biological significance of basic fibroblast growth factor (bFGF)-heparin and heparan sulfate interactions. , 1992, Seminars in cancer biology.

[13]  R. Timpl,et al.  Structural basis and potential role of heparin/heparan sulfate binding to the angiogenesis inhibitor endostatin , 1999, The EMBO journal.

[14]  D. Hicklin,et al.  Heparin modulates the interaction of VEGF165 with soluble and cell associated flk-1 receptors. , 1994, The Journal of biological chemistry.

[15]  R. Timpl,et al.  Crystal structure of the angiogenesis inhibitor endostatin at 1.5 Å resolution , 1998, The EMBO journal.

[16]  M. Steurer,et al.  Angiogenesis as a target for tumor treatment. , 1997, Oncology.

[17]  J. Weiler,et al.  Pattern and spacing of basic amino acids in heparin binding sites. , 1997, Archives of biochemistry and biophysics.

[18]  J. Tam,et al.  Synthetic peptide vaccine design: synthesis and properties of a high-density multiple antigenic peptide system. , 1988, Proceedings of the National Academy of Sciences of the United States of America.